Approach to the Child with Primary Immunodeficiency

Published on 06/06/2015 by admin

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21 Approach to the Child with Primary Immunodeficiency

Lisa Forbes, Terri Brown-Whitehorn

Primary immunodeficiencies are a diverse group of inherited disorders with defects in one or more components of the immune system. Persistent, recurrent, or hard to treat infections are hallmark features of primary immunodeficiency diseases (PIDs). Early diagnosis and referral to a pediatric allergist/immunologist is essential. Treatments such as prophylactic antibiotics or antifungals; immunoglobulin replacement; early recognition of infection; and at times, hematopoietic stem cell transplant can save lives, help prevent infections and end organ damage, and improve long-term outcomes and quality of life.

Primary immunodeficiency disorders are rare, with the exception of IgA deficiency (prevalence of 1 : 500–700 whites). Overall, the incidence of primary immunodeficiency is one in 10,000, with a range of one in 10,000 to one in 200,000. The prevalence differs among ethnic groups and countries of origin. There are approximately 400 new cases of primary immunodeficiency diagnosed in the United States each year. Approximately 80% are diagnosed before 5 years of age. The male-to-female ratio is roughly 2 : 1. According to recent registry data, antibody defects account for 65% of primary immune deficiency, combined defects account for 15%, phagocyte defects account for 10%, complement defects account for 5%, and cellular defects without antibody dysfunction account for 5%. Although immunodeficiency may be secondary to many disease processes, including infection, metabolic disorders, protein-losing states, medications, and oncologic and rheumatologic disorders, this chapter focuses on the approach to the PIDs.

Etiology and Pathogenesis

The pathogenesis of primary immune defects is related to the underlying cellular defect, which may be further divided into problems with the innate and adaptive immune system. Immune defects are distinguished by the cellular mechanism involved, including B cells and humoral or antibody defects, T cells and cell-mediated defects, combined B and T cell defects, phagocytic defects, complement defects, and newly described defects in pattern recognition molecules (Toll-like receptors [TLRs] and signaling molecules). The innate immune system is composed of phagocytes (dendritic cells, macrophages, and neutrophils), complement components, natural killer (NK) cells, TLRs, and signaling molecules. These cells are the first line of defense and respond to pathogens in a nonspecific manner. The adaptive immune system includes B cells, T cells, and combined defects. These cells recognize and respond to pathogens in a specific manner, leading to long-lasting immunity. There are also genetic disorders of immune regulation that cross both arms of the immune system. Specific disorders are often associated with particular infectious organisms (Table 21-1).

Table 21-1 Infectious Organisms Associated with Immunodeficiency

Disorders of the Innate Immune System

Phagocytes

Phagocytes are responsible for detecting and migrating to the site of intruder by recognition of microbial products, antibody-mediated detection, or complement. In turn, these cells produce cytokines and signal the adaptive immune system to fight an infection or react to the danger signal. Abnormalities lead to severe and unusual infections. Representative disorders include congenital neutropenia, chronic granulomatous disease, and hyper immunoglobulin E (IgE) syndrome. Four specific genetic defects in phagocyte NADPH oxidase have been described in chronic granulomatous disease. A neutrophil defect should be considered in children who have recurrent abscesses, Staphylococcus infections, granulomas, and an unusual sensitivity to Aspergillus or atypical mycobacterium.

Natural Killer Cells

NK cells confer immunity against viruses, intracellular bacteria, and parasites and provide cytotoxicity against tumor cells. The three disorders that affect NK cells and related interferon gamma (INF-γ)/interleukin-12 (IL-12) pathway are NK cell deficiency (e.g., CD16 deficiency), IFN-γ receptor 1 and 2 defects, and Griscelli syndrome (albinism with immunodeficiency). Patients with defects in the IFN-γ/IL-12 pathway typically present with atypical mycobacterium infection. Patients with isolated NK cell defects are susceptible to herpes viral infections.

Complement

The complement system shares responsibility in host defense, induction of the adaptive immune system, inflammation, and clearance of apoptotic cells and immune complexes. The clinical manifestations of deficiencies early in the complement cascade are susceptibility to infections with Streptococcus pneumoniae and Haemophilus influenzae and rheumatologic abnormalities, such as systemic lupus erythematosus (see Chapter 29). Neisseria infections are more common with defects in later components of the complement cascade. Hereditary angioedema results from a defect in C1 esterase inhibitor enzyme function.

Toll-like Receptors

TLRs are a recently discovered component of the innate immune system. They are a family of pattern recognition receptors whose sole job is immunologic surveillance. TLRs recognize microbial products and danger signals and activate pathways that produce cytokines to recruit the appropriate immune response. Most defects in the TLRs or signaling molecules downstream affect children early in life until the adaptive immune system can mature and contribute to immune regulation. IRAK-4 (interleukin-1 receptor-associated kinase 4) deficiency is an example of a specific defect of the TLR pathway.

Disorders of the Adaptive Immune System

Humoral Immune System

The humoral immune system defects, including B cell and antibody defects, make up the most common PIDs. These defects include selective IgA deficiency, transient hypogammaglobulinemia of infancy, X-linked agammaglobulinemia (XLA, or Bruton agammaglobulinemia), hyper IgM syndrome (CD40 ligand deficiency), IgG subclass deficiency, selective antibody deficiency, and common variable immune deficiency (CVID). Patients with humoral defects are typically older than 6 months; they may be diagnosed in the toddler or school-age group. Although CVID can be diagnosed at an earlier age, it is typically diagnosed in adolescents and adults. Children with transient hypogammaglobulinemia of infancy have low quantitative IgG levels with normal IgG function, as noted by protective titers to immunization. Over time, the quantity of IgG normalizes. Children with other humoral defects are unable to respond normally to bacterial infections. Specific defects have been described for some disorders. In XLA, the absence of the Btk gene leads to impairment in B cell development, maturation, function, and receptor signaling. Diagnosis is made by absence of mature B cells. Patients with hyper IgM most commonly have a defect in CD40 ligand (on T cells). Without CD40 ligand binding to CD40 on B cells, the normal switch from IgM to IgG or IgA does not occur. In CVID, patients may have normal mature B cells. However, they have defects in differentiation to immunoglobulin-secreting plasma cells. Characteristic infections seen in humoral defects include severe enteroviral infections in patients with XLA, Pneumocystis carinii pneumonia or Cryptosporidium parvum (associated with sclerosing cholangitis) in patients with hyper IgM, and Giardia infections in patients with XLA or CVID. In addition to infection, some of these patients are more at risk for autoimmune disease and malignancy.

Cell-Mediated Immune System

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